PROJECT SUMMARY The overarching goal of this project is to develop new catalysts and reactions to empower the chemical synthesis of biologically active natural product targets and pharmaceuticals. In particular, we formulate a rationale for designing strained and bridged bicyclic phosphine oxides that can be readily reduced back to phosphines after the phosphine oxides are formed in situ. A new bridged [2.2.1] bicyclic phosphine oxide has already displayed reactivity, in both catalytic Wittig and Staudinger reactions, superior to that of the best alternatives known today. Experimental and theoretical investigations have predicted that the proposed [2.1.1] bicyclic phosphine oxides would be even more reactive. Considering the ubiquity of reactions driven by the formation of phosphine oxides (e.g., Staudinger, Wittig, Mitsunobu, and Appel reactions), and their environmental consequences, our proposed research should have significant impact on organic synthesis. Our inspiration for the bridged [2.2.1] bicyclic phosphine oxide originated from the trans-4-hydroxy-L-proline (Hyp)?derived chiral phosphines we developed during the last funding period. Building on the greater faculty of the [2.2.1] bicyclic phosphine oxide, we will apply the Hyp-derived 2-aza-5-phosphabicyclo[2.2.1]heptanes to catalytic asymmetric Staudinger, Wittig, Mitsunobu, and Appel reactions. These chiral phosphines have already exhibited tremendous potential in facilitating enantioselective Mitsunobu and Appel reactions and the first successful example of a catalytic asymmetric Staudinger/aza-Wittig reaction. We will also create new bridged [2.2.1] bicyclic chiral phosphines from carvone. Carvone-derived P-chiral phosphines should be versatile catalysts because both enantiomers of carvone are naturally abundant and, therefore, inexpensive. Capitalizing on the capacity of phosphines to serve as both organic catalysts and ligands on homogeneous transition metal catalysts, we propose to develop a tandem Michael-Heck reaction of alkenyl halides and activated acetylenes for the assembly of 5- and 6-membered carbo- and heterocycles. One particular Michael-Heck process employing iodoalcohols is a powerful tool for assembling furans of almost any substitution pattern and provides access to several structurally disparate furanosesquiterpenoid natural products. We have already made 10 different Hyp-derived chiral phosphines commercially available through Sigma?Aldrich and will collaborate with them again to make our phosphine oxides and chiral phosphines available to the scientific community. Many research groups have already used Hyp-derived phosphines in a variety of catalysis reactions. We anticipate that the proposed research will have a similar significant impact on chemical synthesis. Collectively, the catalysts and reactions developed in this application will allow the enantioselective preparation of medicinally significant pharmaceuticals and natural product targets.